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Drug Therapy Drug Therapy Aztreonam bile, bronchial and intestinal secretions. Concentrations in lung, bile and peritoneal fluid are nearly equal to that of serum(3). It Seema Kapoor crosses the blood brain barrier and achieves Geeta Gathwala therapeutic levels in the cerebrospinal fluid(1.4 micrograms/ml)(4,5). Aztreonam penetrates into cerebrospinal fluid (CSF) more rapidly in patients with inflamed meninges(6). Aztreonam belongs to the monobactam group of It is also active across a wide range of pH naturally occurring antibiotic compounds values, making it a useful adjunct in the characterized by a monocycling ring structure. Aztreonam is the first monobactam that has been treatment of abscesses. After intramuscular approved for use in pediatric medicine by US FDA in injection, absorption is almost complete. the year 1998. Absorption after intraperitoneal administra- tion in patients with peritonitis is 92%. Over a Mechanism of Action large dosage range, plasma concentrations increase in direct proportion to the dose. Aztreonam is a bactericidal antibiotic, Diffusion across the placenta is poor, as is which interferes with the synthesis of the diffusion into breast milk. The serum half life bacterial cell wall(1), the mechanism being is 2.4 to 5.7 hours for preterm infants during similar to that of penicillins and cephalo- the first week of life. In contrast, the mean half sporins. It binds preferentially to the Penicillin life is 1.7 hours for patients older than one binding protein-3 (PBP-3) of gram negative month but younger than 12 years of age. bacteria and causes lysis and death. There is Elimination of Aztreonam is primarily renal, poor affinity of Aztreonam for the PBP’s of with glomerular filtration and secretion gram positive and anaerobic bacteria, which playing equal roles. Sixty to seventy percent of accounts for its narrow spectrum of the administered dose is excreted in the urine activity(2). This drug is stable to hydrolysis by unchanged(8). In patients with impaired renal chromosomal or plasmid mediated beta function, serum aztreonam concentrations are lactamases of gram negative species and does higher, and the half life is extended(9). not induce chromosomal beta lactamase production. Spectrum of Activity Pharmacokinetics Aztreonam has excellent activity against Aztreonam is not absorbed orally. It is major gram negative pathogens like E. coli, distributed in most of the body fluids including Klebsiella species, H. influenzae, Serratia bone, blister fluid, bile, bronchial and species and Pseudomonas aeruginosa. For intestinal secretions. Concentrations in lung, Pseudomonas, the minimum bactericidal concentration (MBC) is generally 4-16 times Correspondence to: Dr. Seema Kapoor, M-439, Guru greater than the MIC(1,11). Established Harikrishan Nagar, Paschim Vihar, New Delhi susceptibility breakpoints for Aztreonam 110 087. using agar and broth dilutions are 8 µg/ml or INDIAN PEDIATRICS 359 VOLUME 41__ APRIL17, 2004 DRUG THERAPY less (susceptible), 16 µg/ml (intermediate) and Aztreonam was well tolerated and safe in 32 µg/ml or greater (resistant). The majority premature infants when a glucose solution of Enterobacteriacae, notably E. coli, K. (>5 mg/kg/minute) was concomitantly pneumoniae and Citrobacter species are infused(17). inhibited by less than 1 µg/ml of Aztreo- There have been no reports of ototoxicity nam(12). Serratia and Enterobacter are less or nephrotoxicity associated with Aztreonam, susceptible (MIC 1 to 4 µg/ml), whereas 90 nor have there been severe hematological H. influenzae and N. gonorrhea are more abnormalities associated with its use. Central susceptible (MIC £0.25 µg/ml). Pseudo- 90 nervous system side effects are reported monas aerugionosa requires the MIC’s in the rarely, and these tend to be minimal. Hepatic range of 8 to 12 µg/ml of Aztreonam. toxicity with transient elevation of trans- Side Effects aminases and alkaline phosphatase, is seen occasionally, but it reverts to normal values on The safety profile of Aztreonam has been cessation of therapy(18). Aztreonam contains well studied. Adverse reactions occur in a beta lactam ring and therefore has a potential approximately 7-12% of pediatric patients, but for cross allergenicity with penicillins and only 2% are serious enough to warrant cephalosporins. However studies have shown discontinuation of the drug(13). It is well that fewer than 1% of beta lactam allergic tolerated with no apparent side effects when individuals given Aztreonam had a possible given intravenously to newborns(14). The hypersensitive reaction. Caution is advised in most commonly reported adverse reactions in patients with known immediate type adults were local, consisting of phlebitis or hypersensitivity reaction to penicillins and intramuscular injection site discomfort. In US cephalosporins and therapy should be pediatric clinical trials, neutropenia occurred discontinued at the first sign of allergic in 11.3% patients younger than 2 years reaction(19). Bacterial superinfection with receiving 30 mg/kg every 6 hrs. AST and ALT aztreonam monotherapy is unusual, but when elevations to greater than 3 times the upper present it is usually because of gram positive limit of normal were noted in 15-20% patients organisms and fungi. aged 2 years and above only when receiving more than 50 mg/kg every 6 hrs. These Therapeutic Uses adverse events were reported with increased Aztrenoam has been used successfully in severity of illness or increased dose. the treatment of a variety of infections such as bacterimias, urinary tract infections, pelvic Systemic reactions such as mild rash, and intra abdominal infections and respiratory nausea, vomiting and diarrhea were reported infections. As Aztreonam’s activity is limited in the same trial. Because Aztreonam has no to the aerobic gram-negative bacilli, it is effect on anaerobic bowel flora, the risk of often used in combination with other drugs Clostridium defiicile colitis from Aztreonam depending on the site of infection. monotherapy is low(15). Aztreonam also contains 780 mg of Arginine per gram of (a) Urinary tract infections: There is exten- antibiotic, and concern has been raised sive clinical experience with aztreonam in regarding possible side effects such as the treatment of both upper and lower Arginine induced hypoglycemia(16). A recent urinary tract infections(20,21). Its efficacy study addressing this safety issue indicate that is comparable to that of second generation INDIAN PEDIATRICS 360 VOLUME 41__ APRIL17, 2004 DRUG THERAPY cephalosporins and aminoglycosides strains of E. coli, Proteus, Klebsiella against common gram negative pathogens. serratia and even Pseudomonas have been Aztreonam is particularly useful as treated with Aztreonam(25). Since bone monotherapy for nosocomial urinary tract and joint infections often require infections that are resistant to other agents prolonged therapy, Aztreonam is a viable or in situations where the risk of toxicity alternative to aminoglycosides in this from aminoglycosides is high(19). Aztreo- setting. In situations, where possibility nam reaches high urinary concentrations of gram positive infection also exists, and hence can be given in a b.i.d. dosage an antistaphyloccal agent should be schedule. added. (b) Bacterimia: Aztreonam has been found to (e) Central Nervous System: Aztreonam has be effective in the treatment of gram been shown to penetrate inflamed negative bacterimia(22). Data from a meninges, and reach therapeutic levels in prospective randomized study of 58 the central nervous system. It is neonates with infection caused by gram- bactericidal against many pathogens negative bacilli including Pseudomonas implicated in gram negative meningitis aeruginosa, suggest that the use of with good activity against N. meningitides. Aztreonam in combination with ampicillin is as efficacious as the standard ampicillin (f ) Gastrointestinal System: It is effective and amikacin regime. A combination of against Campylobacter, Salmonella and aztreobnam with piperacillin was studied Shigella. With the upsurge of multi drug in children with febrile neutropenia resistant Shigella and Salmonella, it forms a and was suggested as first line therapy useful adjunct to therapy of gastro- as it averted aminoglycoside related intestinal organisms(26). In a study toxicity(23). comparing the efficacy, safety and cost of cefixime, cefriaxone and aztreonam in (c) Lower Respiratory Infections: Aztreonam the treatment of multidrug resistant when used empirically for the treatment of Salmonella typhi septicemia in children the lower respiratory infections should always authors concluded that ceftriaxone was the be combined with agents active against most cost-effective on an inpatient basis, gram positive and anaerobic organisms. It because of a more rapid clinical cure, and possesses no activity against Mycoplasma, cefixime was the most effective on an Legionella or Chlamydia. Hence, outpatient basis, because of the drug cost. Aztreonam should not be used if these However, aztreonam could be used as infections are suspected. Aztreonam second line therapy in cases of cefriaxone readily penetrates bronchial secretions and failure(27). lung tissue. In nosocomial pneumonias, it can be used in combination with anti (g) Specific situations: (a) ICU setting: pseudomonal penicillins and third genera- Serratia is a common organism causing tion cephalosporins. Clinical trials show it nosocomial infection due to different to be as effective as aminoglycosides(24). portal of entry and studies indicate
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